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MEDI-NEWS

November 2009

Angiotensin II has long been recognized as a key driver in the cardiovascular disease (CVD) continuum that runs from risk factors through to atherosclerosis or organ damage to the manifestation of clinical events and, ultimately, death. The rationale behind the development of specific and selective AT₁ receptor blockade grew out of an understanding that blunting the production of angiotensin II through ACE inhibition may induce an “escape phenomenon” which allows for the production of angiotensin II through alternative pathways. In contrast, specific and selective blockade of AT₁ receptors through angiotensin II receptor blockers (ARBs) stimulates AT₂ receptors and this action is believed to promote positive biologic effects including vasodilatation and inhibition of fibrosis and inflammation.

Nevertheless, as reviewed by Van Liefde and Vauquelin (Mol Cell Endocrinol 2009;302:237-43), a number of studies have explored additional pharmacological properties of the ARBs, with special focus on their “insurmountable antagonism,” i.e. angiotensin II cannot overcome receptor blockade once the antagonist is in place. The degree of insurmountability is also linked to the dissociation rate of the ARB from the AT₁ receptor (Figure 1).

Competitive binding studies have consistently revealed the same order of potency for the ARBs, with candesartan as the most potent, followed by olmesartan, EXP3174 (the active metabolite of losartan), valsartan, irbesartan and losartan. Indeed, the active metabolite of losartan is approximately two times less potent than candesartan and—despite the same dissociation rate and extent of insurmountability as EXP3174—telmisartan is about 10 times less potent than candesartan.

There are also “marked differences” in the ability of different ARB/AT₁ receptor complexes to adopt a slow-dissociating state and in the dissociation rate thereof, as the authors noted. 

Findings from SCOPE and Other Trials

In reviewing the principal randomized trials involving the ARBs, Verdecchia et al. (Vasc Health Risk Manag 2009;5:939-48) looked at several studies involving high-CVD risk hypertensive patients, including the Study on Cognition and Prognosis in the Elderly (SCOPE). Almost 5000 patients between the ages of 70 and 89 received candesartan titrated to 16 mg/day or placebo on top of other antihypertensive agents, as needed.

At a mean follow-up of 3.7 years, 26.7% of patients in the ARB group and 30% in the placebo group (84% of whom were on active drug therapy) reached the primary outcome of CV death, non-fatal stroke and non-fatal myocardial infarction (MI), for a 10.9% risk reduction in favour of the ARB. Active therapy also reduced nonfatal stroke by 27.8% and all stroke by 23.6%.

The same group reviewed the Losartan Intervention for End Point Reduction (LIFE) study in hypertensive patients with left ventricular hypertrophy who received losartan titrated up to 100 mg/day or atenolol at the same uptitrated dose. At a mean of 4.8 years, stroke was the only component of the primary end point which was significantly reduced by losartan compared with atenolol. 

Figure 1.

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study involving over 15,000 hypertensive patients 50 years of age and older compared valsartan 80 to 160 mg/day to amlodipine 5 to 10 mg/day. At a mean of 4.2 years, almost equal percentages in both groups experienced the primary composite end point even though blood pressure was better controlled in the amlodipine arm.

The JIKEI study included Japanese patients who were already receiving conventional treatment for hypertension, coronary artery disease (CAD) or heart failure. Results indicated that fewer of those patients who received additional valsartan reached the primary end point at a median follow-up of 3.1 years compared with those who did not receive an ARB. This difference was largely driven by a 40% reduction in stroke and transient ischemic attack.

In the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET), there was no difference between the two arms in the rates of patients achieving the primary end point, although the incidence of adverse events was higher in the combination arm.

The same team of reviewers also presented evidence supporting a reduction in clinical end points with specific ARBs elsewhere along the CVD continuum, including trials using losartan in ELITE, valsartan in VAL-HeFT and candesartan in CHARM (all heart failure trials). The bottom line for each point of intervention along the CVD continuum was that the effect of specific ARBs on different end points was variable and that physicians should not assume therapeutic benefit demonstrated for one ARB extends to others in the same class.

“In deciding the choice of the ARB in the individual patient… the driving concept should be that, despite the shared mechanism of action, each molecule is characterized by specific pharmacological properties that are likely to influence its clinical efficacy,” the authors concluded. “…Applying conclusions of studies conducted in specific clinical settings with a specific ARB to different contexts or to different ARBs should be avoided.”

Comparison Findings

Given that there have been no controlled randomized, double-blind comparative studies between the ARBs in hypertension, physicians need to look elsewhere for comparative data. When such data do materialize, it is important to keep in mind that hard clinical end points, and not simply blood pressure control, is the only outcome that really matters in the treatment of hypertension. Thus, results from a comparison of two ARBs in the primary treatment of hypertension has important clinical implications. In this recent trial, Kjeldsen et al. (J Hum Hypertens Nov 2009; Epub ahead of print) tested the hypothesis that losartan and candesartan have different effects on CVD risk reduction in a real-life setting of hypertensive patients.

A total of 72 primary care centres in Sweden were screened for patients who had been prescribed either ARB between 1999 and 2007. Among some 14,100 patients diagnosed with hypertension, 7329 were treated with candesartan and 6771 were treated with losartan. Patients were then linked to Swedish national hospitalization and cause-of-death registers.

As investigators reported, there were no differences in blood pressure reduction between the two groups during the study interval. The number of discontinued patients was significantly higher in the losartan group (31.4%) compared to the candesartan group (27.5%), the authors observed. “Patients who were initially treated with losartan were also more frequently converted to another renin-angiotensin system inhibitor compared with candesartan-treated patients (13.9% vs. 10.8%).”

At a median follow-up of two years (maximum nine years), 676 CVD events had occurred in the losartan group vs. 575 in the candesartan group. The cumulative incidence of the primary composite end point (CVD morbidity, CVD mortality and elective coronary revascularization procedures) was 14% lower (HR 0.86) in the candesartan group compared with the losartan group (Figure 2), as was the cumulative incidence of heart failure (36% lower), cardiac arrhythmias (20% lower) and peripheral arterial
er).  

Figure 2.

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Cardiac Remodelling

As the authors noted, both ARBs had a positive effect on cardiac remodelling. The lower risk of cardiac arrhythmias seen in the candesartan group might be explained by the lower incidence of heart failure with this particular ARB. (Alternatively, the lower incidence of atrial fibrillation may explain the lower risk of heart failure.) Still, as they observed, “We believe that the lower risk of new heart failure and cardiac arrhythmias in the candesartan group may be due to a more potent inhibition of AT₁ receptors, as [these end points] occurred at the same level of blood pressure control and in patient groups with similar baseline characteristics.” The researchers also suggested that the lower risk of PAD seen in the candesartan group may be the result of the lower risk of heart failure in this group, as reduced peripheral circulation in patients with heart failure could lead to earlier ischemic symptoms in the lower limbs.

“The results of this study suggest that there is a blood pressure-independent risk reduction in CVD with candesartan compared to losartan in the primary treatment of hypertension,” investigators concluded. They added that results also suggest “pharmacological differences within the ARB class may translate into important clinical effects.”

Questions and Answers

This question-and-answer session was conducted with Dr. Peter Lin, Director, Primary Care Initiatives, Canadian Heart Research Centre, Toronto, Ontario; Dr. Victor Huckell, Clinical Professor of Medicine, University of British Columbia, Vancouver; and Dr. Guy Tremblay, Professor of Medicine, Université Laval, Quebec City, Quebec.

Q: Family physicians are the first line of defence in managing hypertension. What should these study findings be telling them?

Dr. Lin: The Swedish study is very interesting because it’s in real-life patients where they were managed in a way that is more familiar to us in family practice. So it tells us, first of all, that you need to add a diuretic more often when you are using losartan to get to the same blood pressure effect as with candesartan. In the study, patients on both sides did get to the same level of blood pressure so we would have expected the same result because we’ve been told that only  blood pressure matters, but this study shows us that there are benefits beyond blood pressure which means that how you get there is important as well.

Dr. Huckell: In family medicine, there are really only two main issues with blood pressure: Can you use an ARB instead of an ACE inhibitor and can you start with an ARB? The trials say that the efficacy of the ACE inhibitors and the ARBs in general are the same for the prevention of complications of hypertension. As initial monotherapy, the trials also say that physicians can feel comfortable starting with an ARB as a first-line therapy but then the question becomes, are the benefits seen in clinical trials a class effect or not? If you are using an ARB initially, you need to pick a good one based on clinical trial results.

Dr. Tremblay: Family physicians (FPs) are responsible for 85% to 90% of the burden of CVD care and they have to make important decisions about asymptomatic patients. As specialists, we see patients who are already suffering from CVD so it’s easier for us to convince our patients to take medication over time, but FPs are dealing with asymptomatic subjects and they need to have confidence that they will not only lower BP with a good medication but lower CVD risk as well. And they are in fact doing a remarkable job at controlling blood pressure. In the previous Canadian Heart study, only about 13% of patients had their blood pressure controlled but according to more recent data, up to 66% of patients now have their blood pressure controlled so Canadian GPs are taking blood pressure control seriously and they are controlling it at world-record levels. I think this study will reinforce their attitude and skill to achieve good blood pressure control.

Q: The risk reduction in CVD in favour of candesartan in the Swedish study was mainly determined by reductions in arrhythmias, heart failure and PAD. Could you elaborate on how candesartan might have led to these benefits?

Dr. Lin: We now know that within the ARB class, there are differences among the classmates. So the sartans are similar but one difference between them is how well they bind to the AT₁ receptor because if they do not bind tightly to it, they can be bumped off by angiotensin II. We used to talk about the concept of “insurmountable binding” so some ARBs are strong binders to the receptor; others, such as losartan—though not its metabolite which binds more strongly—are weaker binders, so there are basic scientific differences between the molecules which could have possible clinical implications.

Dr. Huckell: We know that when you activate the AT₁ receptor, you get a whole series of reactions including inflammation, thrombosis, vasoconstriction and neurohormonal activation, none of which are good. So if you block the activation of these effects, you are less likely to get arrhythmias and scar tissue down the line and blood pressure goes down as well. As for PAD, we also know that renin system agents help people live longer because they have fewer heart attacks and strokes. Clinical data also suggest the ARBs improve symptoms specific to PAD like intermittent claudication. That is why our guidelines remind us that these agents are mandatory in patients with atherosclerosis. Nevertheless, there is some evidence that not all binding is “insurmountable” and that candesartan sticks to its guns longer than the others, so that is probably an additional benefit.

Dr. Tremblay: We always look for pleiotropic effects of a drug to explain their benefit but we have to remember that candesartan is well proven to achieve 24-hour blood pressure control and even good blood pressure control when patients miss a pill. So this effect is well documented and I think that explains a lot of its benefit over losartan. In addition, more patients on losartan had to have additional diuretics to achieve good blood pressure control and it’s well established that the diuretics have adverse metabolic consequences which would again favour candesartan. But the tighter binding affinity that candesartan has at the AT₁ receptor relative to losartan may explain some of its benefit as well.

Q: Do you think that physicians should avoid attributing protective benefits seen with one ARB to other members of the class?

Dr. Lin: I think what the trial is telling us is that when we make choices for our patients in our own practices, there may be clinical consequences that we may not have considered before. This is [in contrast] to the artificial setting of clinical trials which do not always apply to our own patients. So these real-life studies are important because they tell us what is probably happening in our own practice and in general practice elsewhere and not what has happened in a clinical trial. And in this particular trial, we learned that there are differences between the ARBs so benefit is not necessarily a class effect.

Dr. Huckell: In the theoretical world, you could probably say that the benefits with the ARBs are probably a class effect, but you have to do the trials and if a company hasn’t done a study, then they should not say that their drug is good for a particular indication when they haven’t shown it to be so. So yes, there are subtle differences between the ARBs and I absolutely think we should avoid attributing benefits seen with one ARB to other members of the class.

Dr. Tremblay: Canadian physicians are always looking for the best evidence to justify treatment decisions; for example, they have endorsed the use of ramipril based on the HOPE study, as it was a well-done Canadian trial. Randomized controlled trials show us how efficacious a drug might be but the magic of this Swedish study was that it was done across a large population of hypertensive patients; it involved large practices with large numbers of patients and physicians; and it showed us how efficacious the treatment was. So investigators took a good treatment proven to be efficacious in a research setting and then transplanted it to a real-world setting where it was again shown to be of benefit.